The present invention relates to methods of making quinoline amides. The present invention also relates to compounds that are used to make quinoline amides and methods of making these compounds.
Quinoline amides of Formula I and Ia (R3 is hydrogen) below are microsomal triglyceride transfer protein (MTP) inhibitors and can be used to treat hypercholesterolemia, atherosclerosis, obesity, hyperlipidemia, hypertriglyceridemia, hypoalphalipoproteinemia, pancreatitis, diabetes, stroke, restenosis, or Syndrome X. 
wherein
each R3 is independently hydrogen or C1-C6alkyl;
A is 
X is O or S;
n is 0 to 6;
each Rb is independently hydrogen, xe2x80x94CF3, xe2x80x94OC1-C6alkyl, halo, xe2x80x94SH, xe2x80x94SC1-C6alkyl, phenyl, or xe2x80x94C1-C6alkyl;
B is hydrogen, 
each R is independently hydrogen or C1-C6alkyl;
each Y is independently phenyl, substituted phenyl, pyridyl or substituted pyridyl, wherein from 1 to 3 substituents are independently selected from xe2x80x94CF3, halo,
xe2x80x94OC1-C6alkyl, or xe2x80x94C1-C6alkyl; and
m is 0 to 5.
U.S. patents that disclose MTP inhibitors include U.S. Pat. Nos. 5,919,795, 5,595,872, 5,721,279, 5,739,135, and 5,789,197.
U.S. provisional patent application No. 60/164,803 discloses compounds of Formula I and sets forth specific methods of making the compounds disclosed in the application by starting with 4-hydroxy-7-nitro-quinoline-3-carboxylic acid ethyl ester, which is a known compound [C. C. Price et al., Journal of the American Chemical Society, 69, 374-376 (1947)]. In one aspect, the present invention concerns improved methods of making compounds of Formula I. Unlike the method disclosed in the provisional application, the present methods do not require starting with 4-hydroxy-7-nitro-quinoline-3-carboxylic acid ethyl ester, which is made using a high temperature cyclization to form the quinoline ring system. In addition, the present methods require fewer steps and form the quinoline ring system directly.
The present invention provides a method of making a compound of Formula 
wherein
each R3 is independently hydrogen or C1-C6alkyl;
A is 
X is O or S;
n is 0 to 6;
each Rb is independently hydrogen, xe2x80x94CF3, xe2x80x94OC1-C6alkyl, halo, xe2x80x94SH, xe2x80x94SC1-C6alkyl, phenyl, or xe2x80x94C1-C6alkyl;
B is hydrogen, 
each R is independently hydrogen or C1-C6alkyl;
each Y is independently phenyl, substituted phenyl, pyridyl or substituted pyridyl, wherein any substituents are independently selected from xe2x80x94CF3, halo, xe2x80x94OC1-C6alkyl, or xe2x80x94C1-C6alkyl; and
m is 0 to 5;
the method comprising the steps of:
a. reacting 
b. reducing 
c. reacting 
d. oxidizing 
e. coupling 
In a preferred embodiment of the method, A is 
The present invention also provides the compounds: 
The present invention also provides the compound: 
Also provided is a method of making 
the method comprising the step of:
a. reacting 
Also provided is a method of making 
the method comprising the steps of:
a. reacting 
b. reducing 
Also provided is a method of making 
the method comprising the steps of:
a. reacting 
b. reducing 
c. reacting 
Also provided is a method of making 
the method comprising the step of:
reacting 
xe2x80x83to form 
Also provided is a method of making a compound of Formula I 
wherein
each R3 is independently hydrogen or C1-C6alkyl;
A is 
X is or S;
n is 0 to 6;
each Rb is independently hydrogen, xe2x80x94CF3, xe2x80x94OC1-C6alkyl, halo, xe2x80x94SH, xe2x80x94SC1-C6alkyl, phenyl, or xe2x80x94C1-C6alkyl;
B is hydrogen, 
each R is independently hydrogen or C1-C6alkyl;
each Y is independently phenyl, substituted phenyl, pyridyl or substituted pyridyl, wherein any substituents are independently selected from xe2x80x94CF3, halo, xe2x80x94OC1-C6alkyl, or xe2x80x94C1-C6alkyl; and
m is 0 to 5;
the method comprising the steps of:
1. reacting 
2. reacting 
xe2x80x83to give 
3. hydrolyzing 
xe2x80x83to give 
4. reacting 
xe2x80x83with H2Nxe2x80x94B to provide a compound of Formula I.
In a preferred embodiment of the method, in step 1, the compound poly(4-vinylpyridine) is used a base.
In another preferred embodiment of the method, in step 2 the 
is the sodium salt and C1-C6alkyl is ethyl.
In another preferred embodiment of the method, R3 is hydrogen, A is 
Also provided is the compound: 
Also provided is a method of making 
the method comprising the step of:
reacting 
Also provided is a method of making a compound of Formula I 
wherein
each R3 is independently hydrogen or C1-C6alkyl;
A is 
X is O or S;
n is 0 to 6;
each Rb is independently hydrogen, xe2x80x94CF3, xe2x80x94OC1-C6alkyl, halo, xe2x80x94SH, xe2x80x94SC1-C6alkyl, phenyl, or xe2x80x94C1-C6alkyl;
B is hydrogen, 
each R is independently hydrogen or C1-C6alkyl;
each Y is independently phenyl, substituted phenyl, pyridyl or substituted pyridyl, wherein any substituents are independently selected from xe2x80x94CF3, halo, xe2x80x94OC1-C6alkyl, or xe2x80x94C1-C6alkyl; and
m is 0 to 5;
the method comprising the steps of:
A. reacting 
B. hydrolyzing 
C. reacting 
D. hydrolyzing 
E. reacting 
xe2x80x83with H2Nxe2x80x94B to provide a compound of Formula I.
The present invention also provides the compounds: 
wherein R3 is hydrogen or C1-C6alkyl.
In a preferred embodiment of the immediately preceding compounds, R3 is hydrogen and C1-C6 alkyl is ethyl.
Also provided is a method of making 
wherein R3 is hydrogen or C1-C6alkyl,
the method comprising the steps of:
a. reacting 
Also provided is a method of resolving phenyl-(2-pyridyl)-methylamine to obtain (S)-phenyl-(2-pyridyl)-methylamine, (S)-(+)-xcex1-methoxyphenylacetic acid salt, the method comprising the steps of:
a. reacting phenyl-(2-pyridyl)-methylamine
xe2x80x83with (S)-(+)-xcex1-methoxyphenylacetic acid in isopropanol, which results in a precipitate being formed; and
b. isolating the precipitate, which is (S)-phenyl-(2-pyridyl)-methylamine, (S)-(+)-xcex1-methoxyphenylacetic acid salt.
In a preferred embodiment of the resolution method, the (S)-(+)-xcex1-methoxyphenylacetic acid is present in the reaction in an amount in the range of about 0.5 equivalents with respect to the amine.
In another preferred embodiment of the resolution, the isolated precipitate is purified by recrystallization.
The present invention provides methods of making compounds of Formula I and Formula Ia (R3 is hydrogen). The compounds of Formula I and Ia are inhibitors of microsomal triglyceride transfer protein (MTP) and can be used as pharmaceutical agents to treat diseases such as hypercholesterolemia, atherosclerosis, obesity, hyperlipidemia, hypertriglyceridemia, hypoalphalipoproteinemia, pancreatitis, diabetes, stroke, restenosis, and Syndrome X.
In addition, the present invention provides compounds that are intermediates used in the synthesis of compounds of Formula I and Ia and methods of making these intermediates.
The following terms are used in the application and are defined below.
The term xe2x80x9calkylxe2x80x9d means a straight or branched chain hydrocarbon. Representative examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, and hexyl. Preferred alkyl groups are C1-C6alkyl.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d means fluorine, chlorine, bromine or iodine.
The term xe2x80x9ccycloalkylxe2x80x9d means a cyclic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The term bicycloalkyl means a cyclic hydrocarbon that contains bridging atoms. Examples of bicycloalkyl groups include bicyclo [3.2.1] octane and bicyclo [1.1.0] butane.
The symbol xe2x80x9cxe2x80x94xe2x80x9d means a covalent bond.
In one embodiment, the present invention provides a method of making compounds of Formula Ia, 
wherein
each R3 is independently hydrogen or C1-C6alkyl;
A is 
X is O or S;
n is 0 to 6;
each Rb is independently hydrogen, xe2x80x94CF3, xe2x80x94OC1-C6alkyl, halo, xe2x80x94SH, xe2x80x94SC1-C6alkyl, phenyl, or xe2x80x94C1-C6alkyl;
B is hydrogen, 
each R is independently hydrogen or C1-C6alkyl;
each Y is independently phenyl, substituted phenyl, pyridyl or substituted pyridyl, wherein any substituents are independently selected from xe2x80x94CF3, halo, xe2x80x94OC1-C6alkyl, or xe2x80x94C1-C6alkyl; and
m is 0 to 5;
the method comprising the steps of:
a. reacting 
b. reducing 
c. reacting 
d. oxidizing 
e. coupling 
xe2x80x83with H2Nxe2x80x94B to form a compound of Formula Ia.
In step a of the above method, the nitro amide compound can be made by coupling 3-nitroaniline (Aldrich, Milwaukee, Wis.) with an acid chloride. An acid chloride, which is an activated carboxylic acid, can be made from the corresponding carboxylic acid following procedures that are well known in the art. A preferred acid chloride is 4xe2x80x2-trifluoromethyl-biphenyl-2-carbonyl chloride. Examples of reagents that can be used to make an acid chloride (or acid halide) from an acid include oxalyl chloride, thionyl chloride, PCl3, PBr3, Ph3P in CCl4, and cyanuric fluoride. The coupling of an amine with a carboxylic acid (typically, an activated carboxylic acid such as an acid chloride) is well known in the art. A preferred coupling method of step a of the present invention uses a base such as triethylamine in a polar, aprotic solvent such as tetrahydrofuran. Many procedures that couple a carboxylic acid or derivative with an amine to form an amide have been reported. Many involve the activation of a carboxylic acid to an acid chloride or anhydride followed by coupling with an amine. Many coupling reagents directly activate an acid for reaction with an amine including carbodiimides such as dicyclohexylcarbodiimide (DCC), propanephosphonic anhydride, and various hydroxybenzotriazole derivatives. In many cases it is possible to interconvert from other carboxylic acid derivatives such as an ester, nitrile, or amide to the desired amide. These methods are summarized in Richard C. Larock, Comprehensive Organic Transformations, 2nd ed, Wiley, N.Y., 1999, pp. 1941-1949,1953-1957, 1978-1982,1988-1990, and 1973-1976.
In step b of the above method, the nitro amide made in step a is reduced to an amino amide. The reduction of a nitro group to an amino group is well known to those skilled in the art. For example, in a preferred embodiment of the present invention, palladium dihydroxide (also known as Pearlman""s catalyst) and ammonium formate in a mixture of isopropanol and ethyl acetate can be used. The reduction of an aryl nitro group to an aryl amine has been accomplished in many ways. Common methods include the reduction with a metal catalyst such as palladium on carbon or Rainey nickel and hydrogen gas. Transfer hydrogenation with hydrazine/graphite or cyclohexene/palladium is also effective. Other hydride sources, such as sodium borohydride with various metal salts and lithium aluminum hydride may also be used. Nitro reductions have also been accomplished with zinc or tin and hydrochloric acid. These methods and others are summarized by Richard C. Larock in Comprehensive Organic Transformations, 2nd ed, Wiley, N.Y., 1999, pp. 821-828.
In step c of the above method, a quinoline ring system is formed by reacting the amino amide produced in step b with the diamine reagent (2-dimethylaminomethylene-1,3-bis(dimethylimmonio)propane): 
preferably the bis(tetrafluoroborate) salt (2BF4xe2x88x92). The diamine reagent used in this step can be prepared by reacting bromoacetic acid or bromoacetyl chloride with phosphorus oxychloride and N,N-dimethylformamide, followed by tetrafluoroboric acid. The generation of this reagent is set forth specifically below. The use of this reagent to form the quinoline ring system is advantageous because it does not require a high temperature cyclization step.
In step d above, the newly formed quinoline, which contains an aldehyde group, is oxidized to form a quinoline carboxylic acid. The oxidation of an aldehyde group to a carboxylic acid group is well known to those skilled in the art. A preferred oxidation method of the present invention uses sodium chlorite. Other reagents than can be used to oxidize an aldehyde to a carboxylic acid include potassium permanganate, sodium periodate, ruthenium tetroxide, chromium trioxide, hydrogen peroxide, sodium perchlorate, or the like.
Next, the quinoline carboxylic acid formed in step d above is coupled with an amine having the formula H2Nxe2x80x94B. The coupling of an amine with a carboxylic acid to form an amide is well known to those skilled in the art. A preferred coupling method of the present invention uses 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, triethylamine, and dichloromethane. A preferred amine is phenyl-(2-pyridyl)-methylamine. Many procedures to convert a carboxylic acid or derivative to an amide have been reported as described above.
The present invention is also directed to a method of making compounds of Formula I: 
wherein
each R3 is independently hydrogen or C1-C6alkyl;
A is 
X is O or S;
n is 0 to 6;
each Rb is independently hydrogen, xe2x80x94CF3,xe2x80x94OC1-C6alkyl, halo, xe2x80x94SH, xe2x80x94SC1-C6alkyl, phenyl, or xe2x80x94C1-C6alkyl;
B is hydrogen, 
each R is independently hydrogen or C1-C6alkyl;
each Y is independently phenyl, substituted phenyl, pyridyl or substituted pyridyl, wherein any substituents are independently selected from xe2x80x94CF3, halo, xe2x80x94OC1-C6alkyl, or xe2x80x94C1-C6alkyl; and
m is 0 to 5;
the method comprising:
1.) reacting 
2. reacting 
3. hydrolyzing 
4. reacting 
xe2x80x83with H2Nxe2x80x94B to provide a compound of Formula I.
In step 1 above, an amino aldehyde amide is formed by reacting an acid chloride with 2,4-diaminobenzaldehyde, which is a known compound. [See, for example, Merlic, C. A. et al., J. Org. Chem., 1995, 60, 3365-3369.]. The acid chloride can be formed from the corresponding carboxylic acid by procedures that are well known in the art. 2,4-Diaminobenzaldehyde can also be obtained by reducing 2,4-dinitrobenzaldehyde (Aldrich, Milwaukee, Wis.). Reductions of a nitro group to an amino group are well known. A preferred reduction uses iron dust, glacial acetic acid and ethyl acetate. The reduction of an aryl nitro group to an aryl amine has been accomplished in many ways. Common methods include the reduction with a metal catalyst such as palladium on carbon or Rainey nickel and hydrogen gas. Transfer hydrogenation with hydrazine/graphite or cyclohexene/palladium is also effective. Other hydride sources such as sodium borohydride with various metal salts and lithium aluminum hydride may be used. Nitro reductions have also been accomplished with zinc or tin and hydrochloric acid. These reactions and others are summarized by Richard C. Larock in Comprehensive Organic Transformations, 2nd ed, 1999, pp. 821-828.
The formation of the amino aldehyde amide is accomplished by coupling an acid chloride with an amino group of 2,4-diaminobenzaldehyde. In a preferred embodiment of the method, the coupling is accomplished using poly(4-vinylpyridine). The poly(4-vinylpyridine) (CAS#9017-40-7) can be obtained as 2% or 25% crosslinked with divinylbenzene from Aldrich, Milwaukee, Wis. The use of poly(4-vinylpyridine) provides for greater selectivity with regard to reaction at the 4-amino group of the 2,4-diaminobenzaldehyde.
In step 2 above the amino aldehyde amide is reacted with 
preferably the sodium salt, to provide a quinoline ester. The reaction can be run in glacial acetic acid.
In step 3 above, the quinoline ester is hydrolyzed to form a quinoline carboxylic acid. The hydrolysis of esters is well known to those skilled in the art. Preferred reagents that can be used include a base such as sodium hydroxide in a mixture of methanol and tetrahydrofuran. Other reagents that can be used to hydrolyze an ester to a carboxylic acid include lithium hydroxide, potassium hydroxide or barium hydroxide in methanol, tetrahydrofuran or mixtures thereof. Additional reagents that can be used are set forth in Organic Reactions, 1976, 24, 187; and E. Haslam in Tetrahedron, 1980, 36, 2409-2433.
In step 4 above, the quinoline carboxylic acid is coupled with an amine H2Nxe2x80x94B to provide a compound of Formula I. A preferred amine is phenyl-(2-pyridyl)-methylamine. Many procedures to couple a carboxylic acid or derivative with an amine to form an amide have been reported as described above.
The compounds of Formula I can also be synthesized by the following procedure:
A. reacting 
B. hydrolyzing 
xe2x80x83to form
C. reacting 
D. hydrolyzing 
E. reacting 
xe2x80x83with H2Nxe2x80x94B to provide a compound of Formula I.
In step A above, a halo quinoline ester is reacted with benzophenone imine to form a benzhydrylidene amino quinoline ester. Preferred reagents used to accomplish the reaction include benzophenone imine, tri(dibenzylidieneacetone)dipalladium, 2-(dicyclohexylphosphino)biphenyl, and sodium tert-butoxide in toluene. The halo quinoline ester is known. See, for example, Silva, Y. et al., Acta Cient Venez., 41, 130-131 (1990). Alternatively, the halo quinoline ester can be made by reducing 4-chloro-2-nitrobenzaldehyde to 4-chloro-2-aminobenzaldehyde. 4-Chloro-2-nitrobenzaldehyde can be obtained from P.H.T. International, Inc., Charlotte, N.C. The reduction of a nitro group to an amino group is well known to those skilled in the art. Examples of additional suitable reagents are set forth above. A preferred reduction uses iron powder, hydrochloric acid and a solvent of aqueous ethanol. Next, the 4-chloro-2-aminobenzaldehyde is reacted with 3-hydroxy-acrylic acid ethyl ester, sodium salt, to form the halo quinoline ester.
In step B above, the benzhydrylidene amino quinoline ester is hydrolyzed to form an amino quinoline ester. Preferred hydrolysis reagents are hydrochloric acid and ethanol. Other hydrolysis reagents include mineral acids and water, hydrogen and palladium on carbon, and hydroxylamine.
In step C above, the amino quinoline ester is reacted with an acid chloride to form an amide quinoline ester. Preferred reaction conditions include diisopropylamine in CH2Cl2. The reaction of an acid chloride (i.e., an activated carboxylic acid) with an amine to form an amide is well known to those skilled in the art, and other suitable reagents are set forth above.
In step D above, the amide quinoline ester is hydrolyzed to form an amide quinoline carboxylic acid. Preferred reagents include sodium hydroxide in methanol and tetrahydrofuran. Other reagents that can be used to hydrolyze an ester to a carboxylic acid include lithium hydroxide, potassium hydroxide, barium hydroxide in methanol or tetrahydrofuran or mixtures thereof. Other examples of ester hydrolysis are set forth in Organic Reactions, 1967, 24, 187; and Tetrahedron, 1980, 36, 2409.
In step E above, the amide quinoline carboxylic acid is reacted with an amine of formula HNxe2x80x94B to form a compound of Formula I.
In another aspect, the present invention provides a method of resolving phenyl-(2-pyridyl)-methylamine to obtain the (S)-phenyl-(2-pyridyl)-methylamine, (S)-(+)-xcex1-methoxyphenylacetic acid salt. The resolution method comprises the steps of combining racemic phenyl-(2-pyridyl)-methylamine, which can be obtained from Alfa Aesar, Ward Hill, Mass., and (S)-(+)-xcex1-methoxyphenylacetic acid from Aldrich, Milwaukee, Wis., in isopropanol, which results in the formation of a precipitate, which is (S)-phenyl-(2-pyridyl)-methylamine, (S)-(+)-xcex1-methoxyphenylacetic acid salt. The precipitate is isolated, and can be recrystallized using isopropanol one or more times. Each recrystallization results in a greater enantiomeric purity of the desired (S) isomer of the phenyl-(2-pyridyl)-methylamine salt. It is preferable if about 0.5 mole equivalents of the (S)-(+)-xcex1-methoxyphenylacetic acid is used with regard to the phenyl-(2-pyridyl)-methylamine.
The (S)-phenyl-(2-pyridyl)-methylamine, (S)-(+)-xcex1-methoxyphenylacetic acid salt can be converted to (S)-phenyl-(2-pyridyl)-methylamine hydrochloride salt as detailed below.
All documents cited herein are hereby incorporated by reference.
The examples presented below are intended to illustrate particular embodiments of the invention and are not intended to limit the scope of the specification, including the claims, in any manner.
The following abbreviations are used herein